As biological target molecules to be damaged with free radicals, for example, lipid, sugar, nucleic acid, enzyme, and protein are important. In particular, highly unsaturated fatty acids locally existing in lipids in all cellular membranes are attacked with free radicals, to generate lipid peroxides through lipid peroxidation chain reactions. Direct or indirect actions with these lipid peroxides are considered as one cause of biological membrane damages by free radicals. Biological membrane is composed of lipid and protein, which not only works as a partition wall separating cells and small organs but also forms places with accumulated diverse functions, including for example a source of physiologically active substances or a function as anchors for enzymes and receptors on membrane surfaces. Therefore, lipid peroxidation chain reactions, induced by free radicals, not only give damages to membrane structures but also seriously disrupt enzymatic reactions and receptor functions of proteins, which are working in such membrane structures. When such lipid peroxidation chain reactions occur in any organ or cell, damages naturally occur at that site and sometimes induce a specific disease. Furthermore, it is known that lipid peroxide flows out of local sites into blood circulation, which consequently causes secondary lesions primarily including vascular lesions.
Typical examples thereof are complications of diabetes mellitus, complications of renal impairment, multiple organ impairment during shocks, and the like. Methionine-, histidine-, cystine-, tyrosine- and tryptophan residues are amino acid residues readily oxidizable with free radical and/or active oxygen. Via such oxidative modifications, an enzyme is irreversibly inactivated and simultaneously decomposed readily with protease (such oxidative inactivation of enzymes simultaneously leads to the leukocyte sterilization action).
Meanwhile, nucleic acid damages with free radical and/or active oxygen are very important in view of cancer and aging. It has been demonstrated that free radical and/or active oxygen interacts with and oxidizes any of the bases, sugars and ester bonds of nucleic acids. It is reported that active oxygen generated with xanthine-xanthine oxidase, from leukocyte activated with phorbol ester or from tobacco smoke makes DNA cleavage. As to the role of sugar-derived free radicals in biological organisms, for example, auto-oxidation of glucose, lipid peroxidation and intracellular sugar metabolisms suggest that aldehydes such as glyoxal, methyl glyoxal, glycol aldehyde, 3-deoxyglucoson and glucoson with higher reactivities than those of glucose are deeply involved in the preparation of advanced glycation endproducts (AGE) from proteins. It is considered that the depolymerization of hyauloronic acid with active oxygen is a cause of the reduction of the viscosity of synovial fluid in chronic articular rheumatism. Main diseases specifically involving free radical and/or active oxygen are listed below.
Cataract, damages due to ophthalmologic surgeries, damages with the use of contact lenses, damages due to cornea transplantation, open-angle glaucoma (POAG), corneal diseases, dry eye, bleary eye, macular degeneration, retinal degeneration (age-related macular degeneration), retinopathy of prematurity, eye siderosis, uveal disease, cerebral infarction, cerebral ischemia, cerebral edema, myocardial infarction, ischemic reperfusion disorders, renal reperfusion, arrhythmia, arterial sclerosis, head injuries, cerebral injuries, medulla injuries, rheumatism, inflammation, periodontal disease, odontitis, uveitis, eczema/dermal inflammation, ultraviolet (dermal) damages, autoimmune diseases (rheumatism, etc.), diabetes mellitus, gastritis/gastric ulcer (gastric mucosa damages), liver diseases (drug-induced liver disorders), ulcerative colitis, Crohn's disease (IBD), ischemic colitis, adult respiratory distress syndrome (ARDS), Down syndrome, schizophrenia, epilepsia, neural degeneration diseases, Alzheimer's disease, Parkinson's disease (DIC), aging, amyotropic lateral sclerosis (ALS), hemolytic diseases, disseminated intravascular coagulation (DIC) syndrome, septic shock, traumatic shock, flap necrosis, edema, paraquat poisoning, accelerated vasopermeability, lung emphysema, acute pancreatitis, porphyrrinemia, Mediterranean anemia, and the increase of active oxygen or other free radicals as induced by burn, frostbite, radiation, drugs or hemodialysis (non-patent references 1,2).
Cataract is a disease involving lower vision due to the opacification of ocular lens. Other than the change of the structure via the glycation of ocular lens proteins, the involvement of oxidative stress is remarked as the etiology (non-patent reference 3). Near-ultraviolet ray at 300 to 400 nm, which is absorbed into the lens, generates active oxygen to progress the association of lens proteins and lipid peroxidation, so that polymeric substances and insoluble proteins are generated, which work to enhance scattered light/yellow tone (non-patent reference 3). In eyes with cataract in humans compared with normal lens in humans in the same age group, the reduction of the activities of enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPx) or catalase, the decrease of ascorbic acid or glutathione of reduced type (GSH), and the increase of lipid peroxides are observed, as noted (non-patent reference 3).
N-β-Alanyl-5-S-glutathionyl-3,4-dihydroxyphenylalanine (5-S-GAD) is a known compound with pharmacological actions for example antibacterial action and anti-cancer action (patent reference 1, non-patent reference 4), an action functioning for inhibiting the formation of osteoclast (patent reference 2), and an anti-cancer action against melanoma or breast cancer (patent reference 3).    [Non-patent reference 1] Pharma Medica, 8(4), 11-14 (1990).    [Non-patent reference 2] Clinical Neuroscience, 19(5), 520-525 (2001).    [Non-patent reference 3] Exp Eye Res. 2000, 70(1):81-8    [Non-patent reference 4] J. Biol. Chem. 1996, 271:13573-13577.    [Non-patent reference 5] Cancer Sci. 2003, 94(4): 400-4.    [Patent reference 1] Official Gazette of Japanese Patent No. 3634894    [Patent reference 2] Official Gazette of Japanese Patent No. 3586809    [Patent reference 3] JP-A-2001-213799